NCCN Categories of Evidence and Consensus
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.
Cognitive impairment is a common complaint among cancer survivors and may be a consequence of the tumors themselves or direct effects of cancer-related treatment (eg, radiation therapy). This symptom may be especially prominent in survivors of primary central nervous system (CNS) cancers or those with brain metastases. In addition, survivors who never had brain involvement may also report difficulties in cognition.1 For some survivors, symptoms persist over the long term.2 When more severe, the presence of cognitive dysfunction can impact quality of life and function. Cognitive dysfunction is most commonly connected with chemotherapy (sometimes referred to as “chemobrain”), but evidence suggests that therapies other than chemotherapy, such as endocrine therapy and radiation, may be associated with cognitive impairments.3-9 A recent national cross-sectional study found that a history of cancer is independently associated with a 40% increase of the likelihood of self-reported memory problems.10
Cancer-related cognitive changes have primarily been studied in patients with CNS and breast cancers and lymphoma, and those who have undergone hematopoietic stem cell transplant (HSCT), with a wide incidence ranging from 19% to 78%.2,11-24 Deficits commonly occur in the domains of executive function, learning and memory, attention, and processing speed.2,23
Growing evidence supports the patient experience of cognitive dysfunction associated with cancer and its treatment. In one meta-analysis of 17 studies, women treated with chemotherapy for breast cancer 6 or more months previously (n=807) had lower functional abilities than those not treated with chemotherapy (n=291).14 These deficits were limited to verbal (eg, word-finding) and visuospatial (eg, copying complex images) abilities. However, when compared with their prechemotherapy baseline, no differences were noted among patients complaining of cognitive dysfunction. In another study, cognitive function was compared among 196 long-term survivors of breast cancer treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) who were, on average, 21 years out from diagnosis, and 1509 control patients with no history of cancer.25 The chemotherapy group did significantly worse on several neuropsychological tests (eg, immediate and delayed verbal memory, executive functioning, psychomotor speed). Finally, one study compared 101 patients who underwent an HSCT with 82 patients treated with a nonmyeloablative therapy; both groups showed mild cognitive impairments at baseline.26 Although no significant differences in cognitive dysfunction were identified at 2-year follow-up, patients who underwent HSCT had poorer performances in several areas, including attention and executive and psychomotor functions.
The correlation between patient reports of cognitive decline and results of neuropsychological testing has not been consistently demonstrated, possibly because of various definitions of cognitive dysfunction and differences in the statistical analyses across studies.23 However, a recent study of 189 breast cancer survivors found that memory and executive function complaints, present in approximately 20% of the cohort, showed a statistically significant association with results of domain-specific neuropsychological tests.27
The underlying mechanisms that might increase the risk for chemotherapy-induced cognitive changes are not known. Studies have reported elevated levels of cytokines or DNA damage as some of the possible mechanisms.28 Structural studies have supported the hypothesis that neurotoxicity resulting in damage to white matter of the brain may play an important role in cognitive deficits after chemotherapy treatment.2,5,13,29,30 In addition, fatigue and depression, common in cancer survivors, may negatively influence cognitive function, although several studies have found that cognitive dysfunction does not correlate with mood.25,31 Psychosomatic effects can also contribute, as evidenced by a recent study of patients to be treated with chemotherapy, which found that those who were informed of the possible cognitive side effects were more likely to report cognitive dysfunction and perform worse on neuropsychological testing than uninformed patients.32 A better understanding of the mechanisms that cause cancer-related cognitive impairment is essential for the development of treatments to improve cognitive function and quality of life in patients with cancer and survivors.1,33,34
In October 2006, the International Cognition and Cancer Taskforce (ICCTF) was formed, comprising a multidisciplinary group of health professionals and health advocates. The mission of ICCTF is to advance understanding of the impact of treatment-related cognitive and behavioral functioning in patients with non-CNS cancers.35 The group recently published recommendations regarding neuropsychological testing, defining cognitive impairment/changes, and future study design.34 ICCTF also has a Web site (www.icctf.com) to provide up-to-date information to both physicians and patients seeking assistance in the management of cognitive symptoms associated with cancer treatment.
Janelsins MC, Kohli S, Mohile SG et al.. An update on cancer- and chemotherapy-related cognitive dysfunction: current status. Semin Oncol 2011;38:431–438.
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Ahles TA, Saykin AJ, McDonald BC et al.. Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve. J Clin Oncol 2010;28:4434–4440.
Ahles TA, Root JC, Ryan EL. Cancer- and cancer treatment-associated cognitive change: an update on the state of the science. J Clin Oncol 2012;30:3675–3686.
Hodgson KD, Hutchinson AD, Wilson CJ, Nettelbeck T. A meta-analysis of the effects of chemotherapy on cognition in patients with cancer. Cancer Treat Rev 2012;39:297–304.
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Jean-Pierre P, Winters PC, Ahles TA et al.. Prevalence of self-reported memory problems in adult cancer survivors: a national cross-sectional study. J Oncol Pract 2012;8:30–34.
Ahles TA, Saykin AJ, Furstenberg CT et al.. Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma. J Clin Oncol 2002;20:485–493.
Anderson-Hanley C, Sherman ML, Riggs R et al.. Neuropsychological effects of treatments for adults with cancer: A meta-analysis and review of the literature. J Int Neuropsychol Soc 2003;9:967–982.
Deprez S, Amant F, Smeets A et al.. Longitudinal assessment of chemotherapy-induced structural changes in cerebral white matter and its correlation with impaired cognitive functioning. J Clin Oncol 2012;30:274–281.
Jim HS, Phillips KM, Chait S et al.. Meta-analysis of cognitive functioning in breast cancer survivors previously treated with standard-dose chemotherapy. J Clin Oncol 2012;30:3578–3587.
Jim HS, Small B, Hartman S et al.. Clinical predictors of cognitive function in adults treated with hematopoietic cell transplantation. Cancer 2012;118:3407–3416.
Meadows ME, Chang G, Jones JA et al.. Predictors of neuropsychological change in patients with chronic myelogenous leukemia and myelodysplastic syndrome. Arch Clin Neuropsychol 2013;28:363–374.
Santini B, Talacchi A, Squintani G et al.. Cognitive outcome after awake surgery for tumors in language areas. J Neurooncol 2012;108:319–326.
Satoer D, Vork J, Visch-Brink E et al.. Cognitive functioning early after surgery of gliomas in eloquent areas. J Neurosurg 2012;117:831–838.
Scherwath A, Schirmer L, Kruse M et al.. Cognitive functioning in allogeneic hematopoietic stem cell transplantation recipients and its medical correlates: a prospective multicenter study. Psychooncology 2013;22:1509–1516.
Scoccianti S, Detti B, Cipressi S et al.. Changes in neurocognitive functioning and quality of life in adult patients with brain tumors treated with radiotherapy. J Neurooncol 2012;108:291–308.
Stewart A, Bielajew C, Collins B et al.. A meta-analysis of the neuropsychological effects of adjuvant chemotherapy treatment in women treated for breast cancer. Clin Neuropsychol 2006;20:76–89.
Syrjala KL, Artherholt SB, Kurland BF et al.. Prospective neurocognitive function over 5 years after allogeneic hematopoietic cell transplantation for cancer survivors compared with matched controls at 5 years. J Clin Oncol 2011;29:2397–2404.
Vardy J, Rourke S, Tannock IF. Evaluation of cognitive function associated with chemotherapy: a review of published studies and recommendations for future research. J Clin Oncol 2007;25:2455–2463.
Zucchella C, Bartolo M, Di Lorenzo C et al.. Cognitive impairment in primary brain tumors outpatients: a prospective cross-sectional survey. J Neurooncol 2013;112:455–460.
Koppelmans V, Breteler MM, Boogerd W et al.. Neuropsychological performance in survivors of breast cancer more than 20 years after adjuvant chemotherapy. J Clin Oncol 2012;30:1080–1086.
Harder H, Van Gool AR, Duivenvoorden HJ et al.. Case-referent comparison of cognitive functions in patients receiving haematopoietic stem-cell transplantation for haematological malignancies: two-year follow-up results. Eur J Cancer 2007;43:2052–2059.
Ganz PA, Kwan L, Castellon SA et al.. Cognitive complaints after breast cancer treatments: examining the relationship with neuropsychological test performance. J Natl Cancer Inst 2013;105:791–801.
Deprez S, Billiet T, Sunaert S, Leemans A. Diffusion tensor MRI of chemotherapy-induced cognitive impairment in non-CNS cancer patients: a review. Brain Imaging Behav 2013;7:409–435.
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Schagen SB, Das E, Vermeulen I. Information about chemotherapy-associated cognitive problems contributes to cognitive problems in cancer patients. Psychooncology 2012;21:1132–1135.
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. Player L Mackenzie L Willis K Loh SY Women's experiences of cognitive changes or ‘chemobrain’ following treatment for breast cancer: a role for occupational therapy? [published online ahead of print February 6, 2014]. Aust Occup Ther J, doi: 10.1111/1440-1630.12113.
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